SRF transcriptionally regulates the oligodendrocyte cytoskeleton during CNS myelination (ChIP-Seq)

Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.神经元轴突的髓鞘形成对神经系统发育至关重要。髓鞘形成过程需要少突胶质细胞（oligodendrocytes）发生剧烈的细胞骨架动态重塑，但目前学界对髓鞘形成过程中肌动蛋白的调控机制仍知之甚少。我们近期发现血清反应因子（serum response factor, SRF）——一种在其他细胞类型中已被证实可调控肌动蛋白及肌动蛋白调控因子表达的转录因子——是衰老大脑髓鞘形成的关键驱动因子。然而，我们对SRF在少突胶质细胞谱系细胞中的核心功能仍存在重大认知空白。 本研究证实，发育阶段的髓鞘形成需要少突胶质细胞内SRF的细胞自主性表达。通过将染色质免疫沉淀测序（chromatin immunoprecipitation sequencing, ChIP-seq）与RNA测序（RNA sequencing, RNA-seq）相结合，我们在少突胶质前体细胞（oligodendrocyte progenitor cells, OPCs）和少突胶质细胞中鉴定出SRF的靶基因，其中涵盖肌动蛋白及其他关键细胞骨架相关基因。据此，SRF敲除的少突胶质细胞在分化早期的肌动蛋白丝水平显著下降，这与其在肌动蛋白依赖性髓鞘起始过程中的功能角色相符。 综上，本研究证实SRF是一类转录调控因子，可调控少突胶质细胞中髓鞘形成所需的细胞骨架基因的表达。本研究揭示了一条调控少突胶质细胞生物学特性的全新通路，该通路与大脑发育、衰老及多种疾病均具有高度相关性。